Alzheimer's Disease Hallmarks: Beta-Amyloid in the Hippocampus of TgF344-AD Rats and its Relation to Cognitive Impairment

Abstract

Alzheimers Demens har været kendt i over 100 år, og flere og flere mennesker rammes eftersom mennesker lever længere og længere. Den dag i dag er sygdommen uhelbredelig og kan ikke forebygges, og dens fulde ætiologi er fortsat ukendt. Enorme mængder forskning om Alzheimers Demens udføres hvert år for at lære mere om sygdommen, som frarøver folk deres minder, deres personlighed og deres ældre familiemedlemmer. Der er gjort betydelige fremskridt, og kortlægning af hjernen er kommet langt, hvilket har ledt til muligheder for at lære om Alzheimer Demens in vivo i mennesker. Når det kommer til udvikling af behandlinger, står dyremodeller derimod forrest i feltet, men alligevel har behandlingsparadigmer fejlet gang på gang når de testes på mennesker, på trods af at fungere helt fint i dyremodeller. En mulig forklaring på denne dissonans er, at dyremodellerne måske ikke er komplekse nok til fuldt ud at repræsentere sygdommen. Disse modeller er ganske nok uvurderlige når det kommer til at lære om sygdommens individuelle aspekter, men de er utilstrækkelige modeller for udviklingen af generel behandling for Alzheimers Demens. En meget lovende og relativt ny dyremodel, TgF344-AD rottemodellen, udviklet af Cohen og kollegaer i 2013, byder muligvis på en mere integrativ model, eftersom disse rotter udviser flere tegn på Alzheimers Demens end de fleste andre dyremodeller. Modellen er blevet undersøgt med hensyn til både neuropatologi, kognitive begrænsninger og neuropsykiatriske symptomer, og udviser stort potentiale som et redskab til at lære mere om den sygdom, som plager flere og flere mennesker. Der er dog stadig viden at opnå om denne model. Formålet med dette speciale er at præsentere aktuel viden om Alzheimers Demens, såvel som om TgF344-AD modellen, og at undersøge tilstedeværelsen af beta-amyloid i rotternes hippocampus via immunohistokemi. Yderligere, studiet sammenligner niveauet af beta-amyloid med hukommelsesproblemer, målt på den hippocampusafhængige spatiale hukommelsestest, Barnes Maze. 8 10 måneder gamle TgF344-AD rotter og 8 Fisher 344 vildtype kuldkammerater matchet for alder og køn er anvendt i dette studie. En signifikant forskel i beta-amyloid blev fundet mellem genotyperne; Hvor virtuelt intet var til stede i vildtyperotterne, var gennemsnitligt 9,84% af de transgene rotters hippocampi dækket af plaques. Dette er desuden sammenlignet med tilstedeværelsen af beta-amyloid i en rotte fra et tidligere studie, og metoden immunohistokemi diskuteres. Hvad angår hukommelsesproblemer sås ingen korrelation mellem dette og mængden af beta-amyloid i hippocampus, hvilket stemmer overens med resultater fra studier af menneskelige Alzheimers Demens patienter. Konfunderende faktorer, inklusiv neuropsykiatriske symptomer, diskuteres. Samlet set, bakker dette speciales resultater op om TgF344-AD rottemodellens lovende potentiale, eftersom sygdomsforløbet synes at være sammenligneligt med menneskelige Alzheimers Demens patienters sygdomsforløb på flere områder.

Alzheimer’s Disease has been known for more than 100 years, affecting more and more people as the human population grows ever older. To this day, the disease remains untreatable and unpreventable, and the full etiology has stayed unknown. Immense amounts of research about Alzheimer’s Disease are conducted every year to learn more about the disease that robs people of their memories, their personalities, and their elderly family members. Considerable progress has been made, and brain mapping has come a long way, opening doors for gaining knowledge about human Alzheimer’s Disease in vivo. When it comes to development of treatments, however, animal models of the disease are in the front of the field, yet treatment paradigms have failed repeatedly when applied to humans, in spite of working perfectly well in animal models. One possible reason for such dissonance is that the animal models employed may not be complex enough to fully mirror the disease. Granted, such models are invaluable when it comes to learning about the individual features of the disease, but they cannot stand as adequate models for developing broad treatments for Alzheimer’s Disease. One very promising, fairly recent animal model, the TgF344-AD rat model, developed by Cohen and colleagues in 2013, may provide a better integrative model, as these rats display more features of Alzheimer’s Disease than most other animal models. The model has been investigated with regards to both neuropathology, cognitive impairment, and neuropsychiatric symptoms, and shows great promise as a tool in the process of learning more about the disease that plagues more and more humans. Nonetheless, there is still knowledge to gain about this model. The aim of this thesis is to present current knowledge about Alzheimer’s Disease, as well as the TgF344-AD model, and to examine the presence of beta-amyloid in the hippocampus of the rats via immunohistochemistry. Furthermore, the study compares the beta-amyloid levels with impairments in memory, measured on the hippocampus-dependent spatial memory test, Barnes Maze. 8 10-month-old TgF344-AD rats and 8 Fisher 344 wildtype littermates matched for age and gender are employed in the study. A significant difference in beta-amyloid is found between the genotypes, with virtually none being present in the wildtype littermates, whereas on average 9.84% of the hippocampi of transgenic rats is covered in plaques. This is compared with the presence of beta-amyloid in a rat from a previous study, and the method of immunohistochemistry is discussed. As for memory impairments, no correlation is found with the amount of beta-amyloid present in the hippocampus, which is similar to results found in studies performed on human Alzheimer’s Disease patients. Confounding factors, including neuropsychiatric symptoms, are discussed. In sum, the results of this thesis continue to support the promising potential of the TgF344-AD rat model, as its disease course seems to be comparable with that of human Alzheimer’s Disease patients on several aspects.

A master thesis from Aalborg University

Alzheimer's Disease Hallmarks: Beta-Amyloid in the Hippocampus of TgF344-AD Rats and its Relation to Cognitive Impairment